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1.
Yakugaku Zasshi ; 140(10): 1251-1258, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999204

RESUMO

Natural materials such as crude drugs and foods are mixtures composed of various metabolites. Metabolic profiling is often used to identify possible correlations between a compound's metabolic profile and pharmacologic activity. Direct-injection electron ionization-mass spectrometry (DI-EI-MS) is a novel metabolomics method useful for characterizing biological materials. This review demonstrates the establishment of a DI-EI-MS method for metabolic profiling using several closely related lichen species: Cladonia krempelhuberi, C. gracilis, C. pseudogymnopoda, and C. ramulosa. The qualitative DI-EI-MS method was used to profile major and/or minor constituents in extracts of lichen samples. Each lichen sample could be distinguished by altering the DI-EI-MS electron energy and examining the resulting data using one-way analysis of variance. We also attempted to predict pharmacologic activity using DI-EI-MS metabolomics. Blueberry leaf extracts inhibited the proliferation of adult T-cell leukemia (ATL) cells. Blueberry leaf extracts could be distinguished by principal component analysis based on the absolute intensity of characteristic fragment ions. Twenty cultivars were categorized into four species, and the most appropriate discriminative marker m/z value for identifying each cultivar was selected statistically. Components extracted based on DI-EI-MS analyses could be used to construct a model to predict ATL cell bioactivity. These data suggest that the novel DI-EI-MS metabolomics method is suitable for identifying species of natural materials and predicting their pharmacologic activity. This approach could enhance public health by facilitating evaluations of pharmacologic activity and functionality, leading to the elimination of counterfeit products.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Mirtilos Azuis (Planta)/química , Mirtilos Azuis (Planta)/metabolismo , Líquens/metabolismo , Metabolômica , Extratos Vegetais/farmacologia , Proliferação de Células/efeitos dos fármacos , Previsões , Humanos , Leucemia-Linfoma de Células T do Adulto/patologia , Espectrometria de Massas/métodos , Metabolômica/métodos , Extratos Vegetais/isolamento & purificação
2.
Nat Commun ; 11(1): 4022, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782248

RESUMO

One major bottleneck in natural product drug development is derivatization, which is pivotal for fine tuning lead compounds. A promising solution is modifying the biosynthetic machineries of middle molecules such as macrolides. Although intense studies have established various methodologies for protein engineering of type I modular polyketide synthase(s) (PKSs), the accurate targeting of desired regions in the PKS gene is still challenging due to the high sequence similarity between its modules. Here, we report an innovative technique that adapts in vitro Cas9 reaction and Gibson assembly to edit a target region of the type I modular PKS gene. Proof-of-concept experiments using rapamycin PKS as a template show that heterologous expression of edited biosynthetic gene clusters produced almost all the desired derivatives. Our results are consistent with the promiscuity of modular PKS and thus, our technique will provide a platform to generate rationally designed natural product derivatives for future drug development.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Policetídeo Sintases/genética , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Estrutura Molecular , Família Multigênica/genética , Policetídeo Sintases/metabolismo , Sirolimo/química , Sirolimo/metabolismo , Estereoisomerismo , Streptomyces/enzimologia , Streptomyces/genética , Streptomyces/metabolismo
3.
Nat Commun ; 11(1): 4202, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826900

RESUMO

Antibiotic biosynthetic gene clusters (BGCs) produce bioactive metabolites that impart a fitness advantage to their producer, providing a mechanism for natural selection. This selection drives antibiotic evolution and adapts BGCs for expression in different organisms, potentially providing clues to improve heterologous expression of antibiotics. Here, we use phage-assisted continuous evolution (PACE) to achieve bioactivity-dependent adaptation of the BGC for the antibiotic bicyclomycin (BCM), facilitating improved production in a heterologous host. This proof-of-principle study demonstrates that features of natural bioactivity-dependent evolution can be engineered to access unforeseen routes of improving metabolic pathways and product yields.


Assuntos
Antibacterianos/biossíntese , Vias Biossintéticas/genética , Família Multigênica , Produtos Biológicos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Clonagem Molecular , Escherichia coli , Regulação Bacteriana da Expressão Gênica , Engenharia Metabólica , Pseudomonas fluorescens/genética , Pseudomonas fluorescens/metabolismo
4.
Adv Exp Med Biol ; 1207: 709-724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671788

RESUMO

Anti-cancer effect of natural products has been widely known. As a sort of multi-target anti-cancer agents, natural compound's regulation on autophagy in cancer cells has been studied as a promising research to reveal the mechanism in oncogenesis, as well as a potential short way to anti-cancer drug discovery. In this chapter, we reviewed the cancer-autophagic-related studies on several natural product compounds. It was concluded that natural product compounds directly or indirectly regulated most of the target proteins on the autophagic signal pathways. Considering we have not seen the whole clear atlas of autophagy in oncogenesis yet, it is hard to raise up any conclusion that autophagy is always playing a positive role in oncogenesis and cancer progression.


Assuntos
Autofagia , Produtos Biológicos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
5.
Nat Commun ; 11(1): 3337, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620756

RESUMO

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L-1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.


Assuntos
Alcaloides/biossíntese , Benzilisoquinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Alcaloides/química , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Benzilisoquinolinas/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Engenharia Genética , Modelos Químicos , Estrutura Molecular , Saccharomyces cerevisiae/genética , Tetra-Hidroisoquinolinas/química
6.
Nat Commun ; 11(1): 3091, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555159

RESUMO

Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (-)-variabilin, (-)-homopterocarpin, (-)-medicarpin, (-)-3,9-dihydroxypterocarpan, and (-)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (-)-glyceollin I and (-)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2'-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton.


Assuntos
Isoflavonas/metabolismo , Pterocarpanos/metabolismo , Sesquiterpenos/metabolismo , Produtos Biológicos/metabolismo , Biomimética/métodos , Regulação da Expressão Gênica de Plantas
7.
Nat Commun ; 11(1): 2258, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382158

RESUMO

En route to a bio-based chemical industry, the conversion of fatty acids into building blocks is of particular interest. Enzymatic routes, occurring under mild conditions and excelling by intrinsic selectivity, are particularly attractive. Here we report photoenzymatic cascade reactions to transform unsaturated fatty acids into enantiomerically pure secondary fatty alcohols. In a first step the C=C-double bond is stereoselectively hydrated using oleate hydratases from Lactobacillus reuteri or Stenotrophomonas maltophilia. Also, dihydroxylation mediated by the 5,8-diol synthase from Aspergillus nidulans is demonstrated. The second step comprises decarboxylation of the intermediate hydroxy acids by the photoactivated decarboxylase from Chlorella variabilis NC64A. A broad range of (poly)unsaturated fatty acids can be transformed into enantiomerically pure fatty alcohols in a simple one-pot approach.


Assuntos
Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Álcoois Graxos/química , Álcoois Graxos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Lactobacillus reuteri/metabolismo , Stenotrophomonas maltophilia/metabolismo , Especificidade por Substrato
8.
Nat Biotechnol ; 38(9): 1087-1096, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32440005

RESUMO

Small molecules are usually compared by their chemical structure, but there is no unified analytic framework for representing and comparing their biological activity. We present the Chemical Checker (CC), which provides processed, harmonized and integrated bioactivity data on ~800,000 small molecules. The CC divides data into five levels of increasing complexity, from the chemical properties of compounds to their clinical outcomes. In between, it includes targets, off-targets, networks and cell-level information, such as omics data, growth inhibition and morphology. Bioactivity data are expressed in a vector format, extending the concept of chemical similarity to similarity between bioactivity signatures. We show how CC signatures can aid drug discovery tasks, including target identification and library characterization. We also demonstrate the discovery of compounds that reverse and mimic biological signatures of disease models and genetic perturbations in cases that could not be addressed using chemical information alone. Overall, the CC signatures facilitate the conversion of bioactivity data to a format that is readily amenable to machine learning methods.


Assuntos
Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Bases de Dados Factuais , Descoberta de Drogas , Tratamento Farmacológico , Humanos , Preparações Farmacêuticas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
9.
Nat Chem Biol ; 16(7): 783-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32393899

RESUMO

Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.


Assuntos
Araquidonato 5-Lipoxigenase/química , Produtos Biológicos/química , Inibidores de Lipoxigenase/química , Masoprocol/química , Triterpenos/química , Sítio Alostérico , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Produtos Biológicos/metabolismo , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/metabolismo , Leucotrieno B4/química , Leucotrieno B4/metabolismo , Inibidores de Lipoxigenase/metabolismo , Masoprocol/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Triterpenos/metabolismo
10.
Int J Biol Macromol ; 160: 1-17, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470577

RESUMO

The present-day world is severely suffering from the recently emerged SARS-CoV-2. The lack of prescribed drugs for the deadly virus has stressed the likely need to identify novel inhibitors to alleviate and stop the pandemic. In the present high throughput virtual screening study, we used in silico techniques like receptor-ligand docking, Molecular dynamic (MD), and ADME properties to screen natural compounds. It has been documented that many natural compounds display antiviral activities, including anti-SARS-CoV effect. The present study deals with compounds of Natural Product Activity and Species Source (NPASS) database with known biological activity that probably impedes the activity of six essential enzymes of the virus. Promising drug-like compounds were identified, demonstrating better docking score and binding energy for each druggable targets. After an extensive screening analysis, three novel multi-target natural compounds were predicted to subdue the activity of three/more major drug targets simultaneously. Concerning the utility of natural compounds in the formulation of many therapies, we propose these compounds as excellent lead candidates for the development of therapeutic drugs against SARS-CoV-2.


Assuntos
Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Terapia de Alvo Molecular , Betacoronavirus/enzimologia , Betacoronavirus/fisiologia , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Fatores de Tempo , Interface Usuário-Computador
11.
J Appl Microbiol ; 129(3): 612-625, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32274883

RESUMO

AIMS: Identification of the mycobiota associated to the marine echinoderm Holothuria poli and investigation of cytotoxic and pro-osteogenic potential of isolated strains. METHODS AND RESULTS: Fungal strains were isolated from the animal's body-wall, intestine and faeces. The species identification was based on DNA barcoding and morphophysiological observations. Forty-seven species were identified, all are Ascomycota and mainly belonging to Aspergillus and Penicillium genera. Sixteen strains were grown on three media for chemical extraction. Cytotoxic activity was tested on a hepatic cancer cell line (HepG2), the cells viability was evaluated after treatment using a resazurin based assay (AlamarBlue). Pro-osteogenic activity was tested on human Mesenchymal stem cell, differentiation was measured as the alkaline phosphatase production through reaction with p-nitrophenylphosphate or as the cells ability to mineralize calcium using a colorimetric kit (StanBio). Cytotoxic activity was recorded for four fungal species while five of 48 extracts highlighted bioactivity towards human mesenchymal stem cells. CONCLUSIONS: The presence of relevant animal-associated mycobiota was observed in H. poli and selected strains showed cytotoxic potential and pro-osteogenic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: Our work represents the first report of a Mediterranean Sea cucumber mycobiota and highlights the isolates potential to synthetize compounds of pharmaceutical interest for regenerative medicine.


Assuntos
Produtos Biológicos/farmacologia , Fungos/isolamento & purificação , Fungos/metabolismo , Holothuria/microbiologia , Micobioma , Animais , Produtos Biológicos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Fungos/classificação , Fungos/genética , Células Hep G2 , Humanos , Células-Tronco Mesenquimais , Osteogênese/efeitos dos fármacos
12.
Nature ; 580(7803): 329-338, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296187

RESUMO

The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin-a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of 'rational drug discovery' methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class-being freed from the constraint of having to directly modulate the target upon binding-may enable access to components of the proteome that currently cannot be targeted by drugs.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Animais , Produtos Biológicos/metabolismo , Indústria Farmacêutica , Humanos , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Chem Biol Interact ; 323: 109030, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32205154

RESUMO

The review summarizes literature data on the DNA-binding, DNA-protecting and DNA-damaging activities of a range of natural human endogenous and exogenous compounds. Small natural organic molecules bind DNA in a site-specific mode, by arranging tight touch with the structure of the major and minor grooves, as well as individual bases in the local duplex DNA. Polyphenols are the best-studied exogenous compounds from this point of view. Many of them demonstrate hormetic effects, producing both beneficial and damaging effects. An attempt to establish the dependence of DNA damage or DNA protection on the concentration of the compound turned out to be successful for some polyphenols, daidzein, genistein and resveratrol, which were DNA protecting in low concentrations and DNA damaging in high concentrations. There was no evident dependence on concentration for quercetin and kaempferol. Probably, the DNA-protecting effect is associated with the affinity to DNA. Caffeine and theophylline are DNA binders; at the same time, they favor DNA repair. Although most alkaloids damage DNA, berberine can protect DNA against damage. Among the endogenous compounds, hormones belonging to the amine class, thyroid and steroid hormones appear to bind DNA and produce some DNA damage. Thus, natural compounds continue to reveal beneficial or adverse effects on genome integrity and provide a promising source of therapeutic activities.


Assuntos
Produtos Biológicos/metabolismo , Reparo do DNA , DNA/metabolismo , Alimentos , Compostos Orgânicos/metabolismo , Produtos Biológicos/química , Hormônios/metabolismo , Compostos Orgânicos/química
14.
Poult Sci ; 99(3): 1540-1550, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32111321

RESUMO

This study investigated the influence of meat and bone meal (MBM), phytase, and antibiotics (AB) on the performance, intestinal pH, ileal digestibility, cecal microbiota, and tibial mineralization in Ross 308 broilers challenged with necrotic enteritis (NE). A total of 672-day-old male Ross 308 chicks were allocated to 8 treatments with 6 replicate pens, with 14 birds each. The study employed a 2 × 2 × 2 factorial arrangement of treatments: MBM (no or yes), AB (no or yes, zinc bacitracin + salinomycin), and phytase level (500 or 1,500 FTU/kg; both using 500 matrix recommendations). Diets were based on wheat-soybean meal-canola meal. All birds were challenged with Eimeria spp on day 9 and Clostridium perfringens (C. perfringens) strain EHE-NE18 on day 14 and day 15. On day 21 (postchallenge), birds fed MBM had reduced weight gain (WG; P < 0.05) relative to without MBM. A 2-way phytase × AB interaction for WG on day 14 (P < 0.001) and day 21 (P < 0.001) and feed conversion ratio on day 21 (P < 0.001) and day 42 (P < 0.01) indicated positive effects of high phytase on bird performance in the presence of AB. On day 42, a 3-way MBM × phytase × AB interaction (P < 0.01) was observed for WG, showing high phytase increased WG with AB, relative to the birds without AB in the presence of MBM. A 2-way MBM × phytase interaction (P < 0.01) was observed for apparent ileal digestibility of Ca and P on day 16, whereby there was a notable reduction in Ca and P digestibility in birds fed MBM-free diets and a low phytase level, but with the high phytase level, Ca and P digestibility was not influenced by MBM. In conclusion, in NE challenged birds, high phytase has a beneficial effect on leg health and mineral utilization to the extent that it can replace MBM and has beneficial effects on bird performance in the presence of AB.


Assuntos
6-Fitase/metabolismo , Antibacterianos/metabolismo , Calcificação Fisiológica/fisiologia , Galinhas/fisiologia , Intestinos/fisiologia , Minerais/metabolismo , Doenças das Aves Domésticas/metabolismo , 6-Fitase/administração & dosagem , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Produtos Biológicos/administração & dosagem , Produtos Biológicos/metabolismo , Galinhas/crescimento & desenvolvimento , Infecções por Clostridium/metabolismo , Infecções por Clostridium/veterinária , Clostridium perfringens/fisiologia , Coccidiose/metabolismo , Coccidiose/veterinária , Dieta/veterinária , Suplementos Nutricionais/análise , Digestão/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eimeria/fisiologia , Enterite/veterinária , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Minerais/administração & dosagem , Distribuição Aleatória , Tíbia/fisiologia
15.
Xenobiotica ; 50(9): 1043-1051, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32118504

RESUMO

Pregnane X receptor (PXR) as a ligand dependent transcription factor, is capable of regulating gene expression of cytochromes P450 and transporters involved in xenobiotic/drug metabolism and elimination. Due to the species differences in the regulatory specificity of PXR, gene regulation should not be extrapolated from mammal to fish without research data.The aim of present study was to investigate the effect of 27 natural products on PXR, CYP3A30 and MDR1 genes in channel catfish (Ietalurus punetaus) kidney cells (CC-K). The results showed that bisdemethoxycurcumin, glycyrrhetnic acid, rotenone, artemisinin, dihydroartemisinin, ligustilide and matrine strongly induced the mRNA levels of PXR. Additionally, the up-regulation of CYP3A30 gene ran parallel with PXR gene after the treatment of demethoxycurcumin, glycyrrhetnic acid, artemisinin, matrine, baicalein, schisantherin A, ligustilide, and dihydroartemisinin. Moreover, we found that natural products schisandrin A, schisandrin B, schisandrol A, and schisandrol B significantly up-regulated the mRNA level of MDR1 gene.Our work with a view to provide experimental data support for further research, which will make for the rational application of natural products in channel catfish, such as to avoid adverse herb-drug interactions or accelerating the residue elimination of chemical medicine.


Assuntos
Produtos Biológicos/farmacologia , Biotransformação/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Produtos Biológicos/metabolismo , Linhagem Celular , Ciclo-Octanos/metabolismo , Ciclo-Octanos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dioxóis/metabolismo , Dioxóis/farmacologia , Ictaluridae , Lignanas/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/metabolismo , Compostos Policíclicos/farmacologia , Receptor de Pregnano X/metabolismo
16.
J Nat Med ; 74(3): 501-512, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32180104

RESUMO

Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for diversification of the natural products and improvement of the biological activities. For a decade, the characterization of enzymes and enzymatic synthesis of prenylated compounds by using ABBA-type and DMATS-type PTases have been demonstrated. Here, I introduce several examples of the studies on chemoenzymatic synthesis of unnatural prenylated compounds and the enzyme engineering of ABBA-type and DMATS-type PTases.


Assuntos
Alquil e Aril Transferases/metabolismo , Bactérias/enzimologia , Dimetilaliltranstransferase/metabolismo , Fungos/enzimologia , Engenharia de Proteínas , Bactérias/metabolismo , Produtos Biológicos/metabolismo , Fungos/metabolismo , Prenilação/fisiologia
17.
NPJ Syst Biol Appl ; 6(1): 6, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170148

RESUMO

In biotechnology, the emergence of high-throughput technologies challenges the interpretation of large datasets. One way to identify meaningful outcomes impacting process and product attributes from large datasets is using systems biology tools such as metabolic models. However, these tools are still not fully exploited for this purpose in industrial context due to gaps in our knowledge and technical limitations. In this paper, key aspects restraining the routine implementation of these tools are highlighted in three research fields: monitoring, network science and hybrid modeling. Advances in these fields could expand the current state of systems biology applications in biopharmaceutical industry to address existing challenges in bioprocess development and improvement.


Assuntos
Bioengenharia/métodos , Produtos Biológicos/metabolismo , Biologia de Sistemas/métodos , Produtos Biológicos/farmacologia , Biotecnologia/métodos , Biotecnologia/tendências , Indústrias/tendências , Modelos Biológicos
18.
J Med Chem ; 63(5): 1908-1928, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32023055

RESUMO

After the first seed concept introduced in the 18th century, different disciplines have attributed different names to dual-functional molecules depending on their application, including bioconjugates, bifunctional compounds, multitargeting molecules, chimeras, hybrids, engineered compounds. However, these engineered constructs share a general structure: a first component that targets a specific cell and a second component that exerts the pharmacological activity. A stable or cleavable linker connects the two modules of a chimera. Herein, we discuss the recent advances in the rapidly expanding field of chimeric molecules leveraging chemical biology concepts. This Perspective is focused on bifunctional compounds in which one component is a lead compound or a drug. In detail, we discuss chemical features of chimeric molecules and their use for targeted delivery and for target engagement studies.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/tendências , Animais , Produtos Biológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Estrutura Secundária de Proteína
19.
Sci Rep ; 10(1): 1756, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019976

RESUMO

Streptomyces sp. VN1 was isolated from the coastal region of Phu Yen Province (central Viet Nam). Morphological, physiological, and whole genome phylogenetic analyses suggested that strain Streptomyces sp. VN1 belonged to genus Streptomyces. Whole genome sequencing analysis showed its genome was 8,341,703 base pairs in length with GC content of 72.5%. Diverse metabolites, including cinnamamide, spirotetronate antibiotic lobophorin A, diketopiperazines cyclo-L-proline-L-tyrosine, and a unique furan-type compound were isolated from Streptomyces sp. VN1. Structures of these compounds were studied by HR-Q-TOF ESI/MS/MS and 2D NMR analyses. Bioassay-guided purification yielded a furan-type compound which exhibited in vitro anticancer activity against AGS, HCT116, A375M, U87MG, and A549 cell lines with IC50 values of 40.5, 123.7, 84.67, 50, and 58.64 µM, respectively. In silico genome analysis of the isolated Streptomyces sp. VN1 contained 34 gene clusters responsible for the biosynthesis of known and/or novel secondary metabolites, including different types of terpene, T1PKS, T2PKS, T3PKS, NRPS, and hybrid PKS-NRPS. Genome mining with HR-Q-TOF ESI/MS/MS analysis of the crude extract confirmed the biosynthesis of lobophorin analogs. This study indicates that Streptomyces sp. VN1 is a promising strain for biosynthesis of novel natural products.


Assuntos
Antineoplásicos/metabolismo , Produtos Biológicos/metabolismo , Furanos/metabolismo , Streptomyces/metabolismo , Células A549 , Antibacterianos/metabolismo , Bioensaio/métodos , Linhagem Celular Tumoral , Genoma Bacteriano/genética , Células HCT116 , Humanos , Família Multigênica/genética , Filogenia , Streptomyces/genética
20.
Molecules ; 25(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023950

RESUMO

The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules, the current genomics and transcriptomics revolution has illuminated the untapped biosynthetic potential of many diverse organisms. Today, natural product discovery can be driven by biosynthetic gene cluster (BGC) analysis, which is capable of predicting enzymes that catalyze novel reactions and organisms that synthesize new chemical structures. This approach has been particularly effective in mining bacterial and fungal genomes where it has facilitated the discovery of new molecules, increased the understanding of metabolite assembly, and in some instances uncovered enzymes with intriguing synthetic utility. While relatively less is known about the biosynthetic potential of non-fungal eukaryotes, there is compelling evidence to suggest many encode biosynthetic enzymes that produce molecules with unique bioactivities. In this review, we highlight how the advances in genomics and transcriptomics have aided natural product discovery in sources from eukaryotic lineages. We summarize work that has successfully connected genes to previously identified molecules and how advancing these techniques can lead to genetics-guided discovery of novel chemical structures and reactions distributed throughout the tree of life. Ultimately, we discuss the advantage of increasing the known biosynthetic space to ease access to complex natural and non-natural small molecules.


Assuntos
Produtos Biológicos/metabolismo , Vias Biossintéticas , Descoberta de Drogas , Eucariotos , Perfilação da Expressão Gênica , Genômica , Família Multigênica
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